In 2002, in response to the NIH Roadmap to Molecular Libraries and Imaging, we conceived the process and now have fully established a P50 High Throughput Screening Robotics Core. The new Core represents a multi-departmental effort with fiscal support for establishing the Core coming from P50 funds in combination with the Department of Radiology, Department of Molecular Biology & Pharmacology, and Department of Cell Biology as well as the Howard Hughes Medical Institute. The Dean of Washington University School of Medicine as well as the Director of the Washington University Siteman Cancer Center joined our effort with the commitment of additional funds for further development of the resource. Overall, nearly $2M has been invested in the establishment of this resource. This Core serves as an outstanding on-going example of how our P50 program has leveraged university resources and continues to stimulate interdisciplinary molecular imaging activity throughout the WU campus. Functionally and symbolically, Drs. Helen Piwnica-Worms (Cell Biology), Rafi Kopan (Molecular Biology &Pharmacology), and David Piwnica-Worms (Radiology ) serve as Core Co-Directors with shared administration and scientific oversight of Core activities. This Core is housed in the McDonnell Sciences Building, Room 316, across the street from the East Building Imaging Annex, site of many of the Molecular Imaging Center collaborative activities. Construction of the room and instrument requirements was finished in 2005 and installations of the Beckman Coulter BioMek FX liquid handler as well as an ORCA robot on a 6 ft rail were completed in the summer/fall of 2005. A bio-barrier entryway was constructed and positive-pressure, HEPA filtered air circulation has been installed. Integrated readout and cell culture stations are included with the imaging and analysis instruments. This innovative Core was founded on molecular imaging platforms for readout of a wide range of bio-assays and underpins three of the Research Projects in this application. This Core assures that the personnel and resources for high throughput screening are available to all our ICMIC investigators. Jayne Marasa, senior Core lab manager, directs day-to-day experiments and has optimized several protocols and logistical requirements for our first projects in high throughput screening. Exciting data are now coming on-line during the summer 2006. The Core allows for automated screening of cells cultured in 96 or 384 plate formats and can be applied to multiple investigator-initiated molecular imaging applications arising from P50 investigators and throughout the university community. The applications include: 1) small molecule screens applied to cells engineered by WU investigators for imaging and therapeutic drug leads. 2) small molecule or peptide screens to identify enzyme inhibitors (directed against high priority proteases, kinases, phosphatases, etc.) or modulators of protein-protein interactions. 3) genome-wide siRNA library screens against kinases, phosphatases and E3-ligases in human cells targeting signal transduction, cell growth or cell death responses.